Sherwood E R, Varma T K, Fram R Y, Lin C Y, Koutrouvelis A P, Toliver-Kinsky T E
Department of Anesthesiology, The University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555, USA.
Clin Sci (Lond). 2001 Dec;101(6):541-50.
Glucan phosphate has been shown to enhance antimicrobial immunity in a variety of experimental models. However, the mechanisms by which glucans enhance resistance to infection remain largely unknown. Interferon-gamma (IFN-gamma) is a key regulator of both innate and acquired immunity. Suppression of IFN-gamma production is a prominent feature of the altered immune response that follows major trauma or sepsis. The present studies were designed to determine the effect of glucan phosphate on IFN-gamma expression in normal mice and endotoxin [lipopolysaccharide (LPS)]-tolerant mice. The model of LPS tolerance was used because it results in patterns of cytokine expression similar to those commonly observed following severe trauma or sepsis. Glucan treatment potentiated LPS-induced IFN-gamma expression in control mice. The induction of LPS tolerance resulted in marked suppression of LPS-induced IFN-gamma production. However, co-administration of glucan with LPS, during the tolerance induction phase, attenuated the LPS-tolerant response. Interleukin-12 (IL-12) and IL-18 are important mediators of LPS-induced IFN-gamma production. LPS-induced IL-12 p40 mRNA expression was increased in the spleens of glucan-treated mice compared with controls. Induction of LPS tolerance caused marked suppression of IL-12 production, a response that was attenuated by glucan treatment. IL-18 was constitutively expressed in both control and LPS-tolerant mice, and LPS-induced serum levels of IL-18 were increased in mice treated with glucan. T cells isolated from glucan-treated mice exhibited increased IFN-gamma expression in response to IL-12 and IL-18, as well as increased expression of the IL-12 and IL-18 receptors. The ability of glucan to potentiate IFN-gamma expression in control mice provides a potential mechanism by which glucan enhances antimicrobial immunity. The ability of glucan to attenuate suppressed IFN-gamma expression in LPS-tolerant mice denotes its potential benefit for the treatment of trauma and sepsis-induced immunosuppression.
磷酸葡聚糖已在多种实验模型中显示出可增强抗菌免疫力。然而，葡聚糖增强抗感染能力的机制在很大程度上仍不清楚。γ干扰素（IFN-γ）是先天性免疫和获得性免疫的关键调节因子。抑制IFN-γ的产生是重大创伤或脓毒症后免疫反应改变的一个显著特征。本研究旨在确定磷酸葡聚糖对正常小鼠和内毒素[脂多糖（LPS）]耐受小鼠中IFN-γ表达的影响。采用LPS耐受模型是因为它所导致的细胞因子表达模式与严重创伤或脓毒症后常见的模式相似。葡聚糖处理增强了对照小鼠中LPS诱导的IFN-γ表达。LPS耐受的诱导导致LPS诱导的IFN-γ产生明显受到抑制。然而，在耐受诱导阶段将葡聚糖与LPS共同给药，减弱了LPS耐受反应。白细胞介素-12（IL-12）和IL-18是LPS诱导的IFN-γ产生的重要介质。与对照组相比，葡聚糖处理的小鼠脾脏中LPS诱导的IL-12 p40 mRNA表达增加。LPS耐受的诱导导致IL-12产生明显受到抑制，而葡聚糖处理减弱了这种反应。IL-18在对照小鼠和LPS耐受小鼠中均有组成性表达，并且葡聚糖处理的小鼠中LPS诱导的血清IL-18水平升高。从葡聚糖处理的小鼠中分离出的T细胞对IL-12和IL-18的反应表现出IFN-γ表达增加，以及IL-12和IL-18受体的表达增加。葡聚糖在对照小鼠中增强IFN-γ表达的能力提供了一种潜在机制，通过该机制葡聚糖可增强抗菌免疫力。葡聚糖减弱LPS耐受小鼠中被抑制的IFN-γ表达的能力表明其对治疗创伤和脓毒症诱导的免疫抑制具有潜在益处。
